Human umbilical vein endothelial cell vaccine suppresses the angiogenesis of esophageal squamous cell carcinoma in a humanized mouse model

Liu,Hangfan; Zhao,Jimin; Yang,Yi; Jin,Guoguo; Zhang,Xiaoyan; Wang,Dongyu; Xie,Chao; Liu,Kangdong; Chen,Xinhuan; Li,Xiang; Tian,Fang; Dong,Ziming; Lu,Jing

doi:10.3892/or.2018.6653

Human umbilical vein endothelial cell vaccine suppresses the angiogenesis of esophageal squamous cell carcinoma in a humanized mouse model

Authors:
- Hangfan Liu
- Jimin Zhao
- Yi Yang
- Guoguo Jin
- Xiaoyan Zhang
- Dongyu Wang
- Chao Xie
- Kangdong Liu
- Xinhuan Chen
- Xiang Li
- Fang Tian
- Ziming Dong
- Jing Lu
View Affiliations

Affiliations: Department of Pathophysiology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
Published online on: August 17, 2018 https://doi.org/10.3892/or.2018.6653
Pages: 3006-3014

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The antitumor effect of the human umbilical vein endothelial cell (HUVEC) vaccine has been well documented; however, its anti‑angiogenic effects on human esophageal squamous cell carcinoma (ESCC) have yet to be studied. In the present study, a ‘humanized’ mouse model was established by transplanting NOD/SCID mice with human peripheral blood mononuclear cells (PBMC). After 4 weeks, the level of cluster of differentiation (CD)‑45+ human T‑lymphocytes in mouse peripheral blood was >0.1%, which indicated that mouse reconstruction and the human immune system transformation had been successful. The humanized mice were used to evaluate the anti‑angiogenic effect of the HUVEC vaccine on human ESCC. After immunization with the HUVEC vaccine for 5 consecutive weeks, the humanized mice were subcutaneously transplanted with EC9706 cells. The results indicated that the HUVEC vaccine reduced the size of human esophageal carcinoma xenografts by suppressing angiogenesis. In addition, the HUVEC‑immunized mice exhibited reduced expression of angiogenesis‑associated antigens (vascular endothelial growth factor receptor 2 and VE‑Cadherin) in the tumor specimens, and increased levels of angiogenesis‑associated antibodies in the serum. Notably, the HUVEC vaccine also increased the infiltration of human T‑lymphocytes into the spleen of humanized mice. In conclusion, the present study demonstrated the anti‑angiogenic effect of the HUVEC vaccine on ESCC in a humanized mouse model, and set an experimental foundation for the application of the HUVEC vaccine in ESCC patients.

View Figures

View References

1	Zhang Y: Epidemiology of esophageal cancer. World J Gastroenterol. 19:5598–5606. 2013. View Article : Google Scholar : PubMed/NCBI
2	Pujol JL, De Pas T, Rittmeyer A, Vallieres E, Kubisa B, Levchenko E, Wiesemann S, Masters GA, Shen R, Tjulandin SA, et al: Safety and immunogenicity of the PRAME cancer immunotherapeutic in patients with resected non-small cell lung cancer: A phase I dose escalation study. J Thorac Oncol. 11:2208–2217. 2016. View Article : Google Scholar : PubMed/NCBI
3	Yang Y, Lu J, Liu H, Jin G, Bai R, Li X, Wang D, Zhao J, Huang Y, Liu K, et al: Dendritic cells loading autologous tumor lysate promote tumor angiogenesis. Tumour Biol. 37:15687–15695. 2016. View Article : Google Scholar
4	Weis SM and Cheresh DA: Tumor angiogenesis: Molecular pathways and therapeutic targets. Nat Med. 17:1359–1370. 2011. View Article : Google Scholar : PubMed/NCBI
5	Xu M, Xing Y, Zhou L, Yang X, Yao W, Xiao W, Ge C, Ma Y, Yang J, Wu J, et al: Improved efficacy of therapeutic vaccination with viable human umbilical vein endothelial cells against murine melanoma by introduction of OK432 as adjuvant. Tumour Biol. 34:1399–1408. 2013. View Article : Google Scholar : PubMed/NCBI
6	Tanaka M, Tsuno NH, Fujii T, Todo T, Saito N and Takahashi K: Human umbilical vein endothelial cell vaccine therapy in patients with recurrent glioblastoma. Cancer Sci. 104:200–205. 2013. View Article : Google Scholar : PubMed/NCBI
7	Mu X, Sang Y, Fang C, Shao B, Yang L, Yao K, Zhao X, Gou J, Wei Y, Yi T, et al: Immunotherapy of tumors with human telomerase reverse transcriptase immortalized human umbilical vein endothelial cells. Int J Oncol. 47:1901–1911. 2015. View Article : Google Scholar : PubMed/NCBI
8	Xu M, Zhou L, Zhang P, Lu Y, Ge C, Yao W, Xing Y, Xiao W, Dong Y, Wu J, et al: Enhanced antitumor efficacy by combination treatment with a human umbilical vein endothelial cell vaccine and a tumor cell lysate-based vaccine. Tumour Biol. 34:3173–3182. 2013. View Article : Google Scholar : PubMed/NCBI
9	Ellis LM and Fidler IJ: Finding the tumor copycat. Therapy fails, patients don't. Nat Med. 16:974–975. 2010. View Article : Google Scholar : PubMed/NCBI
10	Sanmamed MF, Rodriguez I, Schalper KA, Onate C, Azpilikueta A, Rodriguez-Ruiz ME, Morales-Kastresana A, Labiano S, Perez-Gracia JL, Martín-Algarra S, et al: Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2^−/−IL2Rγ^null immunodeficient mice. Cancer Res. 75:3466–3478. 2015. View Article : Google Scholar : PubMed/NCBI
11	Theocharides AP, Rongvaux A, Fritsch K, Flavell RA and Manz MG: Humanized hemato-lymphoid system mice. Haematologica. 101:5–19. 2016. View Article : Google Scholar : PubMed/NCBI
12	Liu X, Li H, Liu J, Guan Y, Huang L, Tang H and He J: Immune reconstitution from peripheral blood mononuclear cells inhibits lung carcinoma growth in NOD/SCID mice. Oncol Lett. 8:1638–1644. 2014. View Article : Google Scholar : PubMed/NCBI
13	Banuelos SJ, Shultz LD, Greiner DL, Burzenski LM, Gott B, Lyons BL, Rossini AA and Appel MC: Rejection of human islets and human HLA-A2.1 transgenic mouse islets by alloreactive human lymphocytes in immunodeficient NOD-scid and NOD-Rag1^nullPrf1^null mice. Clin Immunol. 112:273–283. 2004. View Article : Google Scholar : PubMed/NCBI
14	Lu J, Zhao J, Liu K, Zhao J, Yang H, Huang Y, Qin Z, Bai R, Li P, Ma J, et al: MAPK/ERK1/2 signaling mediates endothelial-like differentiation of immature DCs in the microenvironment of esophageal squamous cell carcinoma. Cell Mol Life Sci. 67:2091–2106. 2010. View Article : Google Scholar : PubMed/NCBI
15	Jin G, Zhao J, Yang YI, Liu K, Jiang Y, Zhang X, Zhang Y, Huang Y, Lu J and Dong Z: JAK/STAT3 signaling pathway mediates endothelial-like differentiation of immature dendritic cells. Oncol Lett. 10:3471–3477. 2015. View Article : Google Scholar : PubMed/NCBI
16	King M, Pearson T, Shultz LD, Leif J, Bottino R, Trucco M, Atkinson MA, Wasserfall C, Herold KC, Woodland RT, et al: A new Hu-PBL model for the study of human islet alloreactivity based on NOD-scid mice bearing a targeted mutation in the IL-2 receptor gamma chain gene. Clin Immunol. 126:303–314. 2008. View Article : Google Scholar : PubMed/NCBI
17	Chen XY, Zhang W, Zhang W, Wu S, Bi F, Su YJ, Tan XY, Liu JN and Zhang J: Vaccination with viable human umbilical vein endothelial cells prevents metastatic tumors by attack on tumor vasculature with both cellular and humoral immunity. Clin Cancer Res. 12:5834–5840. 2006. View Article : Google Scholar : PubMed/NCBI
18	Holzapfel BM, Wagner F, Thibaudeau L, Levesque JP and Hutmacher DW: Concise review: Humanized models of tumor immunology in the 21st century: Convergence of cancer research and tissue engineering. Stem Cells. 33:1696–1704. 2015. View Article : Google Scholar : PubMed/NCBI
19	Brehm MA, Shultz LD and Greiner DL: Humanized mouse models to study human diseases. Curr Opin Endocrinol Diabetes Obes. 17:120–125. 2010. View Article : Google Scholar : PubMed/NCBI
20	Shultz LD, Ishikawa F and Greiner DL: Humanized mice in translational biomedical research. Nat Rev Immunol. 7:118–130. 2007. View Article : Google Scholar : PubMed/NCBI
21	Shultz LD, Brehm MA, Garcia-Martinez JV and Greiner DL: Humanized mice for immune system investigation: Progress, promise and challenges. Nat Rev Immunol. 12:786–798. 2012. View Article : Google Scholar : PubMed/NCBI
22	Gong Z, Xu H, Su Y, Wu W, Hao L and Han C: Establishment of a novel bladder cancer xenograft model in humanized immunodeficient mice. Cell Physiol Biochem. 37:1355–1368. 2015. View Article : Google Scholar : PubMed/NCBI
23	Yacoub-Youssef H, Marcheix B, Calise D, Thiers JC, Therville N, Benoist H, Blaes N, Segui B, Dambrin C and Thomsen M: Engraftment of human T, B and NK cells in CB.17 SCID/beige mice by transfer of human spleen cells. Transpl Immunol. 15:157–164. 2005. View Article : Google Scholar : PubMed/NCBI
24	Ji M, Jin X, Phillips P and Yi S: A humanized mouse model to study human immune response in xenotransplantation. Hepatobiliary Pancreat Dis Int. 11:494–498. 2012. View Article : Google Scholar : PubMed/NCBI
25	Folkman J: Angiogenesis: An organizing principle for drug discovery? Nat Rev Drug Discov. 6:273–286. 2007. View Article : Google Scholar : PubMed/NCBI
26	Wei YQ, Wang QR, Zhao X, Yang L, Tian L, Lu Y, Kang B, Lu CJ, Huang MJ, Lou YY, et al: Immunotherapy of tumors with xenogeneic endothelial cells as a vaccine. Nat Med. 6:1160–1166. 2000. View Article : Google Scholar : PubMed/NCBI
27	Peiffer DS, Zimmerman NP, Wang LS, Ransom BW, Carmella SG, Kuo CT, Siddiqui J, Chen JH, Oshima K, Huang YW, et al: Chemoprevention of esophageal cancer with black raspberries, their component anthocyanins, and a major anthocyanin metabolite, protocatechuic acid. Cancer Prev Res. 7:574–584. 2014. View Article : Google Scholar
28	Dejana E and Giampietro C: Vascular endothelial-cadherin and vascular stability. Curr Opin Hematol. 19:218–223. 2012. View Article : Google Scholar : PubMed/NCBI
29	Vestweber D: VE-cadherin: The major endothelial adhesion molecule controlling cellular junctions and blood vessel formation. Arterioscler Thromb Vasc Biol. 28:223–232. 2008. View Article : Google Scholar : PubMed/NCBI
30	Okaji Y, Tsuno NH, Saito S, Yoneyama S, Tanaka M, Nagawa H and Takahashi K: Vaccines targeting tumour angiogenesis-a novel strategy for cancer immunotherapy. Eur J Surg Oncol. 32:363–370. 2006. View Article : Google Scholar : PubMed/NCBI